Halogenated arylalkamine ethers



HALOGENATED ARYLALKAMINE ETHERS Claims. (Cl. 260247.7)

This invention relates to a new class of ethers having highly usefulphysiological activity and more particularly to the aryl ethers of aminoalkanols.

The others of this invention are characterized by the formula:

wherein n is 2-5 inclusive, NA is an amino group which is attached tothe alkylene group through the nitrogen and includes the dialkylamino,morpholinyl, piperidinyl, N-carbethoxypiperazine and pyridinyl groups. Xis halogen and Y is hydrogen, halogen or nitro.

The invention also embraces the non-toxic salts such as the acidaddition salts of the above-identified ethers, e.g. the hydrochloride,the sulfate, the oxalate and the tartrate, and the quaternary ammoniumsalts, e.g. the methiodide and the ethylbromide salts of the ethers.

The compounds in this invention have been found to exhibit strongfungistatic activity against Trichophyton mentagraphytes and Candidaalbicans and in addition they exhibit other physiological activity suchas local anesthesia. v p

The ethers of this invention are prepared by forming an alkali metal oran alkaline earth metal salt of a halogen substituted hydroxyarylcompound, and reacting the resulting salt with an alkamine halide toproduce the aryl ether of the aminoalkanol.

The invention is illustrated in greater detail by the following examplesbut it should be understood that the examples are not intended to be alimitation on the scope of the invention.

EXAMPLE I Z-bromo-4-cyclohexylphenyl 'y-4-morpholinylpropyl etherTwenty-five and four tenths grams (0.1 mole) of 2-bromo-4-cyclohexylphenol and 5.6 grams (0.1 mole) of potassium hydroxideare dissolved in 200 cc. absolute alcohol by refluxing. Then 16.3 grams(0.1 mole) of 'y-4-morpholinylpropyl chloride is added and refluxingcontinued for 24 hours. After cooling and filtering, the filtrate isconcentrated on a steam bath in vacuo. The residue is acidified andether extracted to remove any unchanged starting materials. The aqueouslayer is then made basic with 40% sodium hydroxide solution andextracted into ether. The ethereal solution is dried, concentrated andthe product distilled. The boiling point is 205 C./0.65 mm. n 1.5506.Analysis for C H NBrO .-Theory: C, 59.68; H, 7.38. Found: C, 59.88; H,7.39.

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2,928,832 Patented Mar. 15, 19:60

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2 EXAMPLE n 2-bromo-6-cyclohexylphenyl 'y-4-morpholinylpr0pyl ether2-bromo-4-cyclohexylphenyl 'y-4-carbethoxy-1-piperizinylpropyl etherhydrochloride C H N BrO .HCl.-Theory: C, 53.94; H, 6.99. Found:

EXAMPLE IV ether hydrochloride 2,4-dibrom0-6-cyelohexylphenyl'y-4-morpholinylpropyl The product is prepared by combining equimolarpor-.

tions of 2,4-dibromo-6-cyclohexylphenol and 'y-4-m0rpholinylpropylchloride and separating the product as the hydrochloride salt accordingto the method of Example III. The melting point is 200 C. Analysis for CH NBr O .HCl.-'I'heory: C, 45 .85 H, 5.67. Found:

EXAMPLE V 2,6-dibromo-4-cycl0hexylphenyl 'y-4-m0rph0linylpropyl etherhydrochloride The product is prepared by combining equimolar portions of2,6-dibromo-4-cyclohexylphenol and -4-morpholinylpropyl chloride andseparating the product as the 1 hydrochloride salt according to themethod of Example III. Analysis for C H NB1 O .HCl.Theory: C, 45.85; H,5.67. Found: C, 46.50; H, 5.70.

EXAMPLE VI 2-bromo-4-cyclohexylphenyl y-diethy laminopropyl ether Theproduct is prepared by combining equimolar pore tions of2-bromo-4-cyclohexylphenol and 'y-diethylaminopropyl'chloride accordingto the method of Example I. The boiling point is 203-204 C./2.3 mm.Analysis for C H NBrO.Theory: C, 61.95; H, 8.21. Found:

EXAMPLE VII 4-bromo-2-cyclohexylphenyl -4-morpholinylpr0pyl ether Theproduct is prepared by combining equimolar portions of4-bromo-2-cyclohexylphenol and 'y-4-morpholinylpropyl chloride accordingto the method of Example I. The boiling point is 213 C./2.5 mm.

EXAMPLE VIII 2-nitro-4-chloro-6-cyel0hexylphenyl 'y-4-morph0linylpropylether hydrochloride The product is prepared by combining equimolarportions of 2-nitro-4-chloro-6-cyclohexylphenol and 1 -4-morpholinylpropyl chloride and separating the product as thehydrochloride salt according to the method of Example III. The meltingpoint is 202-203" C. Analysis for C H ClN O Ear-Theory: C, 54.43; H,6.73. Found: C, 54.36; H, 6.88.

EXAMPLE IX Z-chloro-d-cyclohexylplzenyl -4-m0rph0linylpropyl etherhydrochloride The product is prepared by combining equimolar por-' tionsof Z-chloro-fi-cyclohexylphenol and v-d-morpholinylpropyl chloride andseparating the product as the hydrochloride salt according to the methodof Example III. p The melting point is 203-204 C. Analysis for C H NClO.I-ICl.Theory: C, 60.96; H, 7.81. Found: C, 59.80; H, 7.95.

EXAMPLE X 2-bromo 4-cyclohexylphenyl v-Z-piperidylpropyl ether2-bromo-4-cyclohexylphenyl fi-4-morplzolinylbutyl ether The product isprepared according to the method of Example X. The boiling point is232-233 C./2.1 mm. Analysis for C H NBIO P TheOr C, 60.60; H, 7.81.Found: C,61.l3;H,7.74.

EXAMPLE XII 2-bromo-4-cycl0hexylphenyl e-4-morpholinylamyl ether Theproduct is prepared according to the method of Example X. The boilingpoint is 238-240 C./2.0 mm. Analysis for C H NBrO .Theory: C, 61.46; H,7.86. Found: C, 61.53; H, 7.69.

EXAMPLE XHI 2-bromo-4-cyclohexylphenyl 8-4-m0rpholinylethyl ether Theproduct is prepared according to the method of Example X. The boilingpoint is 215 C./2.1 mm. Analysis for C H NBrO .Theory: C, 58.70; H,7.11. Found: C, 58.71; H, 6.80.

This application is a continuation-in-part of the copending applicationunder the same title and by the same inventors, filed April 21, 1954,Serial No. 424,741, now abandoned. Others may practice this invention inany of the numerous ways which will be suggested to one skilled in theart and all such practice is intended to be covered by this invention,provided, however, that it falls within the scope of the appendedclaims.

We claim:

1. A chemical compound selected from the group consisting of basicethers and the non-toxic, acid-addition salts thereof, saidether-shaving the following formula:

. 5 wherein n is 2-5 inclusive, NA is selected from the class consistingof diloweralkylamino, morpholinyl, piperidinyl andN'-carhethoxypiperazinyl, X is halogen selected from the groupconsisting of chloro and bromo, and Y is selected from the groupconsisting of hydrogen, halogen and nitro.

2. A chemical compound having the following formula:

wherein X is bromine selected from the group consisting of ohloro andbromo.

3. 2-bromo-4-cyclohexylphenyl 'y-4-morpholinylpropyl ether.

4. 2,4-dibrorno-6-cyclohexylphenyl propyl ether hydrochloride.

5. Z-bromo-4-cyclohexylphenyl y-4-carbethoXy-1-piperazinylpropyl etherhydrochloride.

6. 2-nitro-4-chloro-6-cyclohexylphenyl -4-1norpholinylpropyl etherhydrochloride.

7. 2-bromo-4-cyclohexylphenyl ether.

8. A non-toxic, acid-addition salt of a chemical compound having thefollowing formula:

' -4-morpholinyl- 'y 1 piperidylpropl V wherein X is bromine.

9. A chemical compound having the following formula I wherein X ishalogen and Y is chlorine.

10. A non-toxic, acid-addition salt of a chemical compound having thefollowing formula :wherein X is halogen and Y is chlorine.

References Cited'in the file of this patent UNITED STATES PATENTS2,679,501 Wcnner May 25, 1954 2,838,510 Suter et al. June 10, 19582,851,460 Bryant et al. Sept. 9, 1958 FOREIGN PATENTS 1,056,793 FranceOct. 28, 1953.

OTHER REFERENCES Burger et al.: I.A.C.S., vol. 67 (1945), pp. 1416-1418.

1. A CHEMICAL COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASICETHERS AND THE NON-TOXIC, ACID-ADDITION SALTS THEREOF, SAID ETHERSHAVING THE FOLLOWING FORMUA: